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PRIZE LECTURE |
1 FMP/MDC (Leibniz-Institut für Molekulare Pharmakologie and Max-Delbrück-Zentrum für Molekulare Medizin), Robert-Rössle Strasse 10, D-13125 Berlin, FRG
Several members of the CLC family of Cl– channels and transporters are expressed in vesicles of the endocytotic–lysosomal pathway, all of which are acidified by V-type proton pumps. These CLC proteins are thought to facilitate vesicular acidification by neutralizing the electric current of the H+-ATPase. Indeed, the disruption of ClC-5 impaired the acidification of endosomes, and the knock-out (KO) of ClC-3 that of endosomes and synaptic vesicles. KO mice are available for all vesicular CLCs (ClC-3 to ClC-7), and ClC-5 and ClC-7, as well as its 
-subunit Ostm1, are mutated in human disease. The associated mouse and human pathologies, ranging from impaired endocytosis and nephrolithiasis (ClC-5) to neurodegeneration (ClC-3), lysosomal storage disease (ClC-6, ClC-7/Ostm1) and osteopetrosis (ClC-7/Ostm1), were crucial in identifying the physiological roles of vesicular CLCs. Whereas the intracellular localization of ClC-6 and ClC-7/Ostm1 precluded biophysical studies, the partial expression of ClC-4 and -5 at the cell surface allowed the detection of strongly outwardly rectifying currents that depended on anions and pH. Surprisingly, ClC-4 and ClC-5 (and probably ClC-3) do not function as Cl– channels, but rather as electrogenic Cl––H+ exchangers. This hints at an important role for luminal chloride in the endosomal–lysosomal system.
(Received 9 November 2006;
accepted after revision 14 November 2006;
first published online 16 November 2006)
Corresponding author T. J. Jentsch: FMP/MDC, Leibniz-Institut für Molekulare Pharmakologie and Max-Delbrück-Zentrum für Molekulare Medizin, Robert-Rössle Strasse 10, D-13125 Berlin, FRG. Email: jentsch{at}fmp-berlin.de
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